Cataracts are an abnormal progressive condition of the lens of the eye, characterized by loss of transparency. A gray-white opacity can be seen within the lens, behind the pupil. Most cataracts are caused by degenerative changes, occurring most often after fifty years of age, however in susceptible patients such as diabetics, cataracts can occur at a much earlier age.
Two types of cataracts have been described: (1) metabolic or juvenile cataracts, which are observed in children and young adults with uncontrolled diabetes, and (2) senile cataracts which are more common than metabolic cataracts. The cataracts in diabetics are similar to the senile cataracts observed in non-diabetic patients but tend to occur at a younger age (e.g. the aging process is accelerated).
The tendency to develop cataracts is inherited and can be accelerated by diseases such as diabetes. If cataracts are untreated, sight is eventually lost. First, vision is blurred, then bright lights glare diffusely, and finally, distortion and double vision may develop.
Previously, cataracts have been treated according to the progressive condition of the lens of the eye. In particular, senile cataracts are usually treated with excision of the lens and prescription of special contact lenses or glasses. The soft cataracts of children and young adults can either be incised and drained or fragmented by ultrasound, followed by irrigation and aspiration of the fragments through a minute incision.
As stated above, the tendency to develop cataracts is inherited and can be accelerated by diseases such as diabetes. Diabetes is the leading cause of blindness in adults and accounts for loss of vision in 8% of those who are legally blind in the United States (Klein and Klein, 1995). Sixty-five percent of diabetic patients develop blindness within five years after detection of proliferative retinopathy (Lavine, 1990). An additional complication of diabetes in the eye is associated with swelling of the lens. This swelling is a result of the accumulation of fructose and sorbitol that increases the osmolality within the lens. As this process continues, lens protein becomes denatured and cataracts form (Lavine, 1990).
Studies of the blood vessels in the eve of an animal model of Type II diabetes, the ZDF/Gmi-fa rat, have demonstrated microscopic vascular changes in the retina, such as an increase in capillary nuclear density and an increase in basement membrane thickness, when compared to non-diabetic control animals (Danis et al., 1993). Danis et al, demonstrated that these animals develop microvascular retinopathy determined morphologically by increases in the numbers of endothelial cells (endothelial hyperplasia) and associated capillaries. A prominent early marker for diabetic retinopathy is pericyte degeneration and the development of pericyte ghosts. Another eye complication seen in this diabetic rat model is the development of cataracts.
Using compounds approved for use in humans and available in the oral. injectable and topical routes, such as tetracycline, to treat diseases or conditions such as cataracts has not been suggested. The compound, tetracycline, exhibits the following general structure: The numbering system of the ring nucleus is as follows: 
Tetracycline as well as the 5-OH (Terramycin) and 7-Cl (Aureomycin) derivatives exist in nature, and are well known antibiotics. Natural tetracyclines can be modified without losing their antibiotic properties, although certain elements of the structure must be retained. The modifications that can and cannot be made to the basic tetracycline structure have been reviewed by Mitscher in The Chemistry of Tetracyclines, Chapter 6, Miarcel Dekker, Publishers, New York (1978). According to Mitscher, the substituents at positions 5-9 of the tetracycline ring system may be modified without the complete loss of antibiotic properties. Changes to the basic ring system or replacement of the substituents at positions 1-4 and 10-12, however, generally lead to synthetic tetracyclines with substantially less or effectively no antimicrobial activity. An example of a chemically modified tetracycline (hereinafter CMT) is 4-dedimethylaminotetracyline which is commonly considered to be a non-antimicrobial tetracycline.
In addition to their antibiotic properties, tetracyclines have been described as having a number of other uses. For example, tetracyclines are also known to inhibit the activity of collagen destructive enzymes such as mammalian collagenase, gelatinase, macrophage elastase and bacterial collagenase. Golub et al., J. Periodoat. Res. 20:12-23 (1985); Golub et al. Crit. Revs. Oral Biol. Med. 2: 297-322 (1991);U.S. Pat. Nos. 4,666,897; 4,704,383; 4,935,411; 4,935,412. In addition, tetracyclines have been known to inhibit wasting and protein degradation in mammalian skeletal muscle, U.S. Pat. No. 5,045,538.
Furthermore, tetracyclines have been shown to enhance bone protein synthesis in U.S. Pat. No. Re. 34,656 and to reduce bone resorption in organ culture in U.S. Pat. No. 4,704,383.
Similarly, U.S. Pat. No. 5,532,227 to Golub et al., discloses that tetracyclines can ameliorate the excessive glycosylation of proteins. In particular, tetracyclines inhibit the excessive collagen cross linking which results from excessive glycosylation of collagen in diabetes.
These properties cause tetracyclines to be useful in treating a number of diseases. For example, there have been a number of suggestions that tetracyclines, including non-antimicrobial tetracyclines, are effective in treating arthritis. See, for example, Greenwald et al., “Tetracyclines Suppress Metalloproteinase Activity in Adjuvant Arthritis and, in Combination with Flurbiprofen. Ameliorate Bone Damage,” Journal of Rheumatology 19:927-938(1992); Greenwald et al., “Treatment of Destructive Arthritic Disorders with MMP Inhibitors: Potential Role of Tetracyclines in, Inhibition of Matrix Metalloproteinases: Therapeutic Potential,” Annals of the New York Academy of Sciences 732: 181-198 (1994); Kloppenburg et al., “Minocycline in Active Rheumatoid Arthritis,” Arthritis Rheum 37:629-636(1994); Ryan et al., “Potential of Tetracycline to Modify Cartilage Breakdown in Osteoarthritis,” Current Opinion in Rheumatology 8: 238-247(1996); O'Dell et al., “Treatment of Early Rheumatoid Arthritis with Minocycline or Placebo,” Arthritis Rheum 40:842-848(1997).,
Tetracyclines have also been suggested for use in treating skin diseases. For example, White et al., Lancet, April29, p. 966 (1989) reports that the tetracycline minocycline is effective in treating dystrophic epidermolysis bullosa, which is a life-threatening skin condition believed to be related to excess collagenase.
The effectiveness of tetracycline in skin disorders has also been studied by Elewski et al., Journal of the American Academy of Dermatology 8:807-812 (1983). Elewski et al. disclosed that tetracycline antibiotics may have anti-inflammatory activity in skin diseases.
Similarly, Plewig et al., Journal of Investigative Dermatology 65:532 (1975), disclose experiments designed to test the hypothesis that antimicrobials are effective in treating inflammatory dermatoses. The experiments of Plewig et al. establish that tetracyclines have anti-inflammatory properties in treating pustules induced by potassium iodide patches.
The use of tetracyclines in combination with non-steroidal anti-inflammatory agents has been studied in the treatment of inflammatory skin disorders caused by acne vulgaris. Wong et al., Journal of American Academy of Dermatology 1: 1076-1081 (1984), studied the combination of tetracycline and ibuprofen and found tetracycline to be an effective agent against acne vulgaris and ibuprofen to be useful in reducing the resulting inflammation by inhibition of cycloxygenase. Funt et al., Journal of the American Academy of Dermatology 13: 524-525 (1985), disclosed similar results by combining antimicrobial doses of minocycline with ibuprofen.
An antimicrobial tetracycline derivative, doxycycline, has been used to inhibit nitrate production. D'Agostino et al., Journal of Infectious Diseases: 177:489-92 (1998), discloses experiments where doxycycline, administered to mice injected with bacterial lipopolysaccharide (hereinafter LPS), exerted a protective effect by inhibiting nitrate production by an IL-10 independent mechanism. Experiments carried out in vitro also showed that doxycycline inhibited nitric oxide synthesis by LPS activated macrophages without enhancing endogenous IL-10 release.
Based on the foregoing, tetracyclines have been found to be effective in different treatments. However, there has been no suggestion whatsoever that tetracyclines can be used to reduce the risk of cataract development in a mammal.
Accordingly, it is one of the purposes of this invention, among others, to provide an economical and relatively uncomplicated method of reducing the risk of cataract development.